Our Research Portfolio

Funding innovative science and research in dystonia and Parkinson’s disease is the hallmark of our grant program. The Bachmann-Strauss Foundation supports individual researchers from around the globe engaged in projects that bring us closer to the cure for these disorders.

Mount Sinai Beth Israel, University of Alabama at Birmingham, University of California, San Francisco, and University of Florida

New York, NY, Birmingham, AL, San Francisco, CA, Gainesville, FL

Predicting Outcomes of Deep Brain Stimulation (DBS) in Dystonia: a Multicenter Study of the Bachmann-Strauss Dystonia and Parkinson's Disease Centers of Excellence

Dystonia is a disabling syndrome characterized by involuntary, sustained muscle contractions causing twisting movements and abnormal postures. Several medical therapies for primary dystonia have shown limited efficacy leaving many patients with a profound disability. Deep brain stimulation (DBS) of the globus pallidus (GPi) has emerged as an effective treatment for medication refractory primary dystonia, however the outcomes are slow, delayed, inconsistent across patients, and there is a lack of predictors for outcomes in individual patients. Several visits are required for postoperative programming before the optimal settings and the optimal contact on the DBS lead providing the best clinical response can be established. There are no acute markers during the programming sessions that seem to predict outcome. The mean clinical improvements have been variable (20-76%). We do not have clear predictors that can a priori identify individuals likely to benefit from this therapy. There are several candidate measures for predicting outcome of DBS in dystonia, and the Bachmann-Strauss Centers have complementary expertise in several areas.

The objective of this collaborative study will be to characterize patients with isolated dystonia treated at the four Bachmann Strauss Dystonia and Parkinson Disease Centers of Excellence. The Centers will create a clinical database and DNA bank that will include all of the dystonia patients treated with DBS currently followed at the Centers as well as new cases receiving DBS surgery. The researchers at the four Centers will screen for known genetic mutations responsible for isolated dystonia. They will also gather data on imaging, VTA and electrophysiological measures from eachof the sites. They will then compare clinical features, surgical outcomes, and stimulation settings between those with identified mutations and those without, and will correlate outcomes with imaging and electrophysiological measures. The genetics, imaging, VTAs and physiology will be used individually, and as a group to determine the value as outcome predictors of dystonia DBS.

Characterization of a Novel Mouse Mutant of the DYT4-Associated Gene Tubb4a

Tubb4a is expressed by specific cell populations within the brain and spinal cord and has been identified as a gene associated with the hereditary dystonia DYT4. The neural processes disrupted by Tubb4a mutations that lead to dystonia are unknown. The lab has generated a mouse mutant of Tubb4a that develops a dystonic phenotype and seeks to better understand the neural circuits and cellular pathways that are disrupted in dystonia. Researchers are using mouse genetics to better characterize and identify the disrupted neural cells. This will lead to better understanding of DYT4 and other dystonias and potentially support development of new therapies

Roy Vincent Sillitoe

Baylor College of Medicine

Houston, Texas

Determining the Trigger for Cerebellar Dystonia

Defects in brain communication are always involved in dystonia. While studies have shown that communication problems in the cerebellum can cause the disease, the mechanism of this defective communication is unclear. Using mouse models, the lab is examining the mechanisms that trigger this cerebellar miscommunication. The lab’s strategy is to manipulate the function of specific connections called synapses. They hypothesize that the cerebellum may have one type of synapse that is extremely susceptible to dystonia pathogenesis. Therefore, altering its function may be a major trigger for the disease. They have found that altering this synapse causes severe dystonia in mice, with a striking similarity to what is observed in humans. This model offers an ideal strategy with which to validate potential treatments.

The neural circuitries that mediate the twisting movements of dystonia are not fully understood. Insight into these circuitries is relevant as they may be involved in various types of dystonia or could form potential new targets for intervention. The lab is using a novel technology, called Designer Receptors Exclusively Activated by Designer Drugs (DREADD), to induce a dystonia-like response in mice by activating small clusters of cholinergic neurons in the spinal cord. These neurons can then be reversibly activated by a designer drug that does not affect other neurons. Following activation, dystonia-like phenotypes are elicited. The lab is examining what changes occur following chronic activation and withdrawal of chronic activation.

John Hardy, PhD

UCL Institute of Neurology

London, United Kingdom

Development of a Neuronal <odel of PANK2 Sssociated Neurodegeneration with Brain Iron Accumulation (NBIA)

Neurodegeneration with brain iron accumulation (NBIA) refers to a group of inherited neurodegenerative diseases characterized by progressive, severe dystonia, parkinsonism and pyramidal signs with accumulation of iron in brain tissue. NBIA is aggressive; there is no effective treatment and most patients die by their early twenties. Genetic mutations in the pantothenate kinase 2 gene (PANK2) are the commonest cause of NBIA. To produce a model of NBIA with a human genetic background, the lab developed specialized cells from NBIA patients with PANK2 mutations. The future plan in these models will be to rescue the neuronal function of PANK2 with certain compounds and to develop other NBIA neuronal lines for investigation.

Narayanan Nandakumar, MD, PhD

University of Iowa

Iowa City, Iowa

Serotonin Neuron and Dyskinesias in Parkinson's Disease

One devastating side effect of treatment for Parkinson’s disease (PD) is dyskinesias, or involuntary movements that are difficult to control. This proposal studies the basic neural circuitry of dyskinesias with the hope of finding new treatments. Specifically, the lab uses cutting-edge techniques in powerful animal models to systematically investigate how neurons that contain the neurotransmitter serotonin contribute to dyskinetic movements. The research team will selectively manipulate serotonin neurons in animal models of PD. The findings could illuminate the basic mechanism of how serotonin neurons influence movement, potentially leading to new, highly targeted therapies for PD and other movement disorders.

Paroxysmal kinesigenic dyskinesia (PKD) is a movement disorder manifest by child onset episodes of choreoathetosis and dystonia precipitated by sudden voluntary movements. Benign infantile convulsions are a part of the phenotype but typically resolve and are sometimes forgotten once a patient is experiencing hundreds of movement disorder attacks each day. The team has cloned the genes causing PKD and a related disorder and generating mouse models for further study, which may lead to better diagnosis and treatment of paroxysmal dyskinesias. In addition, better understanding of dopamine signaling and dysregulation in PKD may provide insights into new treatments for other movement disorders like Parkinson’s disease.

Tatiana Fuchs, PhD

Icahn School of Medicine at Mount Sinai

New York, New York

Gene Discovery in Familial Cervical Dystonia

Cervical dystonia (CD) is one of the most common forms of primary focal dystonia with a prevalence estimated at 30/100,000 in the general population. Treatment is incomplete and empiric. This grant is focused on finding a genetic cause for CD. The lab is using an innovative, powerful technique to screen all genes in ten unrelated familial CD patients to develop a list of potential causative genes. We will screen these genes in other CD patients to identify CD causative gene(s). This research will uncover a new causative gene for CD, contribute to the understanding of disease mechanism and provide a basis for the development of new therapies.

Brian Mathur, PhD

University of Maryland School of Medicine

Baltimore, Maryland

Serotonergic Control of Corticostriatal Synapses in L-DOPA- Induced Dyskinesia

Therapeutic L-DOPA is a treatment for the symptoms of Parkinson’s disease (PD), serving to replenish dopamine levels in the striatum, an area of the brain that is critical to normal motor function. L-DOPA is initially effective in alleviating PD motor symptoms. However, after five to ten years, dyskinesias develop, hampering patient quality of life. Dyskinesia development may be linked to dysfunction in two neurotransmitter systems within the striatum: the serotonin and glutamate systems. The lab is studying how interactions between these two systems contribute to the development of L-DOPA induced dyskinesia in a mouse model of PD.

Aiqun Li, PhD

The New York Stem Cell Foundation

New York, New York

Development of an Automated Process to Obtain Reproducible Panels of Purified Dopamine-Producing Cells for Modeling Parkinson’s Disease

Induced pluripotent stem (iPS) cells provide a novel platform to evaluate how genetic and environmental risk factors contribute to Parkinson’s disease (PD). The lab analyzed whether iPS cell-derived midbrain dopamine-producing (mDA) neurons generated from controls differed from PD patients, including a pair of identical twins (one has PD, the other does not) carrying the missense mutation of glucocerebrosidase (GBA N370S). PD twin-derived mDA neurons were found to have elevated alphasynuclein, decreased GBA activity, low dopamine level and up-regulated monoamine oxidase. The team is determining whether the phenotype is specific to these samples, to those affected by PD who have a GBA mutation, or the broader PD community.

Great advances have been made in discovering genetic events that lead to Parkinson's disease. This study will identify new genes that cause this devastating disease, helping to understand how the disorder starts and possibly leading to improved therapeutic approaches to slowing or even stopping the development of the disease.

Edward Burton, MD, DPhil, MRCP(UK)

University of Pittsburgh

Pittsburgh, Pennsylvania

Generation of Torsin 1 Knockout Zebrafish

The most common genetic form of dystonia, DYT1 dystonia is caused by a change in a gene that carries the instructions necessary for brain cells to make a protein called torsin. Using the zebrafish that makes a protein very similar to human torsin, this research will use the torsin knockout model to determine what torsin does in the brain, and to understand how this goes wrong in DYT1 dystonia. The ultimate goal is to develop new drug treatments for dystonia.

Mark Edwards, PhD, MRCP(UK)

University College, Institute of Neurology

London, England

rTMS for the Treatment of Musician's Dystonia

Musician's dystonia causes involuntary posturing of the affected hand. It has been suggested that involuntary movements develop because inappropriate motor memories that incorporate unwanted actions are formed during music practice under conditions of high anxiety and stress. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation technique which has been shown to influence motor memory retention/consolidation. This study will explore whether rTMS given to patients during active performance of movements that induce dystonia can reduce or abolish the "motor memory" responsible for the abnormal hand posturing.

Alfred Goldberg, PhD

Harvard Medical School

Cambridge, Massachusetts

Role of Nedd4 Activity in Protection Against Alpha-synuclein Accumulation and Parkinson's Disease

Studies have established that the build up of a-synuclein in dopaminergic neurons is a critical contributor in the development of Parkinson's disease. Research indicates that Nedd4 modifies a-synuclein content and its toxicity. This work will test whether it may be possible to enhance Nedd4 activation as a possible therapeutic approach to slow or prevent Parkinson's disease progression in neurons. Such experiments could provide a strong rationale for searching for drugs that bind to this domain and prevent to accumulation of a-synuclein.

Neurodegeneration with brain iron accumulation (NBIA) refers to a group of inherited neurodegenerative diseases characterized by progressive, severe dystonia, parkinsonism. This project seeks to identify and characterize novel genetic causes of NBIA using a set of powerful, complementary genetic techniques. The goal is to accelerate understanding of dystonia at the molecular level and to pave the way for the development of new treatments.

Rachel Saunders-Pullman, MD, MPH**

Beth Israel Medial Center

New York, New York

Phenolypic Spectrum of GNAL and THAP1 Mutation Dystonia

For those with a known genetic etiology, such as dystonia due to DYT1 and DYT6 mutations, information about treatment response, genetic counseling information have been studied. However, in the case of DYT6, the range of features associated with mutations is not well understood. This project will address the clinical features associated with this mutation and hopefully will lead to a better understanding and treatment for dystonia, and will also guide research in understanding the basic mechanisms and developing a cure for this form of dystonia.

Terrence J. Sejnowski, PhD

University of California, San Diego

San Diego, California

Objective Quantification of Phenotypic Expression in Cranial Dystonia

The goal of this study is to evaluate computer-aided video processing of facial muscle activity in cranial dystonia. Although clinicians have become adept at treating cranial dystonia, objective measures of symptom severity and frequency have lagged behind. Ultimately, it is hypothesized that advances in video-processing software can be used for assessing more broadly defined facial dyskinesias, and its spatiotemporal resolution will also facilitate linking pathological patterns of muscle activity to underlying pathophysiology.

Philip Starr, MD, PhD*

University of California, San Francisco

San Francisco, California

Cordial Phase-Amplitude Couling in Patients with Generalized Dystonia

The aim of this work is to understand cortical function in dystonia by studying patients undergoing awake neurosurgery. This study will investigate the cordial activity of patients with generalized dystonia. Deep brain stimulation (DB) is an efficient therapeutic treatment for movement disorders during which brain structures are stimulated electrically to alter the brain activity causing abnormal movement. To improve and develop safer and simpler therapeutic strategies, it is important to better understand the pathophysiology of dystonia, especially at the cordial level.

The discovery of several genetic risk factors and progress on their cell-biological role significantly impact understanding of Parkinson's disease. Strong genetic evidence indicates that mutations in ATP13A2 in Parkinson's disease susceptibility locus lead to the Kufor-Rakeb syndrome (KRS), a severe early-onset autosomal recessive form of Parkinson's disease with dementia. However, the molecular properties of ATP13A2 remain unexplored. Uncovering its cell-biological function and role in neurodegeneration and dementia require the identification of the transported substrate. Transporters are implicated in a variety of human disorders and often, these are considered potential drug targets.

Nicholas Wood, PhD, **MRCP(UK)

University College, Institute of Neurology

London, England

Using Genetic to Understand Dystonia: Characterization of Effect of Mutations in AN03 and Exome Sequencing in Familial Dystonia

Exome sequencing is a relatively new technique that involves reading the most important parts of an individual's genetic code all in one go. Using this technique to identify mutations in the novel gene, ANO3, as the cause of a subset of cases of focal dystonia, the work will investigate the means by which mutations in this gene might lead to dysfunction at the cellular level, and how such dysfunction could be linked to the development of the abnormal movements seen in dystonia.

TorsinB; Essential Role in Disease Pathogenesis and Animal Modeling of DYT1 Dystonia

DYT1 dystonia is a neurodevelopmental disease caused by a deletion in the Tor1, a gene encoding torsinA. The lab has developed a model DYT1 dystonia with overt dystonia-like movements and identified TorsinB as a powerful modifier for the torsinA dysfunction that causes abnormal twisting movements. By dissecting the role of torsinB in contributing to abnormal movements and using this information to develop a novel model, there is the potential to transform research in DYT1 dystonia.

Veronique VanderHorst, MD, PhD**

Beth Israel Deaconess Medical Center

Boston, Massachusetts

Cholinergic Spinal Interneurons Mediating Dystonic Phenotypes

The neural substrate that mediates the twisting movements so characteristic in various types of dystonia is not understood fully. Recently, technology has become available that allows the anatomical and functional dissection of the different cell types in the higher centers of the brain and motor neurons. To gain insight in the role of cholinergic neurons in various types of dystonia, a novel technology called Design Receptors Exclusively Activated by Designer Drugs (DREADD) will be used in combination with high speed video analysis, kinematics and chronic EMG recording to measure dystonic muscle activity. This work has the potential to help in developing more precise and powerful intervention strategies for dystonia.

Neurivascular coupling and flow-metabolism dissociation in a rat model of L-DOPA induced dyskinsia

For the first time, brain-imaging methods similar to those used in human patients will be adapted to the rat. The experimental model will allow the lab to devise new pharmacological treatments targeting the abnormal reactions of cerebral microvessels in L-DOPA-induced dyskinesia. Defining both the mechanisms and the consequences of an altered regulation of rCBF in a rat model of L-DOPA-induced dyskinesia will lead to the identification of novel treatments that can reduce the development of dyskinesia by stabilizing the brain microvasculature.

Muscle movement is controlled by a brain circuit called the basal ganglia, and improper functioning in this motor switchboard leads to movement disorders, such as dystonia - a debilitating neurological movement disorder characterized by repetitive or sustained involuntary muscle contractions that force the body to twist into awkward, irregular postures. By using a genetic animal model of dystonia, Dr. Chan will study the abnormalities of GPe neurons at a cellular and molecular level. By measuring the activity and genetic content of these cells we will begin to pinpoint how and why these cells are different in disease states.

Ruth Chia, PhD

Visiting Fellow, Laboratory of Nemogenetics

National Institute in Aging

Bethesda, Maryland

shRNA kinome screen for the identification of kinase regulators of LRRK2

Mutations in Leucine-rich repeat kinase (LRRK2) cause a significant proportion of inherited Parkinson's Disease (PD). LRRK2 mutation cases are very clinically similar to non-inherited, or sporadic, PD telling us that clues from inherited disease might help develop new therapies for several types of PD. However, there are significant gaps in our knowledge about LRRK2. Addressing these will help to advance towards therapeutics. This project aims to identify how LRRK2 is controlled by other kinases. This will be invaluable knowledge especially when designing LRRK2-specific therapeutics.

Ann M. Graybiel, PhD

Professor, McGovern Institute for Brain Research

Department of Brain and Cognitive Sciences

Massachusetts Institute of Technology

Cambridge, Massachusetts

Striosomc-matrix function as a window into dystonia, L-DOPA induced dyskinesia, and Parkinson's Disease

Dysfunction of the striatum and dopamine neurons is well-known causes of Parkinson's Disease, dystonia, and related disorders. Intriguingly, another prominent striatal feature has also been linked to dystonia, L-DOPA induced dyskinesia and animal models of Parkinson's disease. Dr. Graybiel proposes to record from identified striosome and matrix neurons of rodents during behavioral tasks designed to engage the striatal compartments differentially. The results are expected to illuminate the functional differences between striosomes and matrix, thus opening a new window in the study and treatment of dystonia, L-DOPA induced dyskinesia, Parkinson's disease and related disorders.

Deep brain stimulation (DBS) can be a very effective treatment for certain types of dystonia. Dr. Ruge's work will look at two aspects of DBS peculiar to dystonia. The first is that the response to DBS often takes several weeks to reach maximum benefit. The second is that some people have been implanted for several years. If DBS is turned off after many years, symptoms in some people may not reappear for many days or even weeks. Others, however, regain their symptoms immediately. Researchers suspect that in them the DBS is having some long-term effect on how the brain's activity is organized, maybe gradually changing it back to the pattern seen in healthy volunteers without dystonia. By combining this information with details of exactly where the electrodes are placed in the brain and what stimulation parameters are being used, we will be able to make some predictions about how to optimize and prolong the DBS effect.

Pullani Shashidharan, PhD

Department of Neurology

Mount Sinai School of Medicine

New York, New York

Phenotypic and neurochemical characterization of a rat (knockin) model of DYT1 dystonia

Dystonia is a neurological syndrome characterized by abnormal involuntary movements causing twisting and turning of body parts and can result in contorted postures. Among the various forms of dystonia the early onset dystonia (DYTl) is associated with a deletion mutation in the TORI A gene located on chromosome 9, which codes for a protein called torsinA, whose cellular function is unknown. Symptoms of the disease usually start in the leg, mostly during adolescence, and spread to other body parts, and the subject becomes wheel-chair bound. Dr. Sashidharan's current project will investigate the behavioral, neurochemical and biochemical characteristics of the (knockin) rat model.

Ana Westenberger, PhD

Postdoctoral Fellow, University of Luebeck

Luebeck, Germany

New insights into the genetics and molecular pathways of XDP

X-linked dystonia-parkinsonism (XDP; DYT3) is a neurodegenerative movement disorder inherited in an X-linked recessive manner, due to a genetic founder effect, only in individuals of Filipino ancestry. XDP represents a unique model system to study molecular, cellular, neurophysiological and neuroanatomical mechanisms causing these two important movement disorders. Dr. Westenberger will use three parallel approaches. The results of this study will elucidate the basis of neurodegeneration in XDP and potentially explain cellular pathways that are involved in the occurrence of dystonia and parkinsonism, and suggest specific therapeutic approaches in future studies.

Movement Disorder Fellowship:

Jeff Waugh, MD

Massachusetts General Hospital

Jeff Waugh, MD was awarded the Silverman Family Fellowship for specialty training in movement disorders, important to become an academic pediatric neurologist. Dr. Waugh’s fellowship began at Massachusetts General Hospital (MIT) in 2012. The goal of his work is to gain expertise in the methodology, experimental design, and analysis of brain imaging techniques in movement disorders. He will be co-mentored by two distinguished MIT professors: Nutan Sharma, MD, PhD, Associate Professor of Neurology and Director, Dystonia Clinic in Movement Disorders Program, and Anne J. Blood, PhD, Assistant Professor of Psychiatry and Director, Mood and Motor Control Laboratory.

2012 Special Program Grants

Ellen Hess, PhD

Professor, Department of Pharmacology

Emory University School of Medicine

Atlanta, Georgia

Anti-Dystonia Drug Discovery Program

The Bachmann-Strauss Scientific Advisory Board has announced that the Foundation will continue to fund the, headed by. "My general goal is to understand the pathomechanisms of dystonia by examining the underlying anatomical, physiological and biochemical substrates of the disorder by creating and manipulating mouse models. This strategy allows us to induce or ameliorate motor dysfunction in the context of an intact nervous system revealing potential targets for therapeutics," explained Dr. Hess. For example, her team is currently using behavioral and cellular pharmacology to understand the cellular mechanisms that give rise to hyperactivity. Continuing her Bachmann-Strauss funded research studies, the objective of Dr. Hess's research is to identify drugs that can either move directly into clinical trial or be put forward for product development by a biotechnological or pharmaceutical company. The drug screening protocol created in the first phase of her research has transitioned to the testing of new compounds to alleviate dystonia symptoms in mice. Looking ahead, the Anti-Dystonia Drug Discovery Program plans to make drug screening more widely available to facilitate preclinical testing of novel anti-dystonia compounds.

H.A. Jinnah, MD, PhD

Professor, neurology, human genetics and pediatrics,

Emory University

Atlanta, Georgia

Dystonia Coalition iPS Resource

The goal of Dr. Jinnah’s project is to develop a resource for the collection of skin samples for making fibroblast cultures for dystonia, to create stem cells from these fibroblasts to share with dystonia investigators, and to begin to examine the defects in these cells after they are converted into dopamine neurons. As these cells are made from skins samples of dystonia patients, they will contain the genetic defects responsible for the disorder.

Dr. Bragg’s project will generate iPSCs to different genetic causes of dystonia by turning normal cells into cells with dystonia mutations with TALE nucleases. Essentially they will be able to create iPSCs to any genetic form of dystonia using TALE technology. Dr. Bragg will also collaborate with the Jinnah laboratory in developing and comparing the different dystonia iPSC models. Directly comparing TALE nuclease -generated iPSC lines to ones generated by reprogramming patient fibroblasts can provide a lot of useful information.

The Anti-Dystonia Drug Discovery Program, under the direction of Ellen Hess, PhD, Emory University School of Medicine, completed a second year of research studies to identify drugs that can either move directly into clinical trial or be put forward for product development by a bio-technology or pharmaceutical company. The drug screening protocol created in the first phase of development has transitioned to the testing of new compounds to alleviate dystonia symptoms in mice. The Bachmann-Strauss Foundation continues to fund this important project and is enthusiastic about the potential outcomes.

The Michel J. Fox Foundationreceived a second year grant for Dr. Danna Jennings, principal investigator, to explore the function of the neurotransmitter glutamate, and to evaluate the impact of glutamate antagonists, medications with the potential of reducing dyskinesia in Parkinson’s disease patients. This study has strong potential for developing novel medications that could benefit both dyskinesia and dystonia symptoms. Bachmann-Strauss has partnered with the Michael J. Fox Foundation for many years and continues to be their lead partner in the study of dyskinesia.

GRANTS:

Joshua Berke, PhD

University of Michigan

Ann Arbor, MI

Real-time monitoring of striatonigral and striatopallidal cells in mice with levodopa induced dyskinesias

Prolonged levodopa therapy for Parkinson's disease frequently results in uncontrolled movements called levodopa-induced dyskinesias (LIDs). The brain changes responsible for LIDs are currently unknown. Using state-of-the-art techniques to monitor and manipulate individual neurons, Dr. Berke will test the hypothesis that one specific subtype of basal ganglia cell shows altered activity leading to LIDs. The results are expected to be extremely helpful for the generation of new therapies that either prevent or suppress LIDs.

Xandra Breakefield, PhD, and Naoto Ito, PhD

Massachusetts General Hospital

Cambridge, MA

Exploring the role of Dropsophila dtorsin gene in regulating dopamine metabolism

This study aims to clarify the role of torsin in dopamine metabolism by evaluating dtorsin-deficient flies that the researchers created. Because Drosophila (fruit fly) has one dtorsin gene similar to human DYT1, which is defective in early onset dystonia, the research should aid in evaluating the potential usefulness of drug modulation of dopaminergic neurotransmission in DYT1 patients.

Michelle Ehrlich, MD

Mount Sinai School of Medicine

New York, NY

Regulation of TorsinA in a knockin model of DYT6 dystonia

DYT6 is one of the inherited dystonias, caused by one of several mutations that have been identified in the gene THAP1, which is present in the developing and adult mouse brain. This study will create a genetically accurate mouse model of DYT6, in which regulation and levels of THAP1 will be under normal control in order to determine if this mutation alters the regulation of other genes that are known to play a role in dystonia.

Phyllis Hanson, MD, PhD

Washington University School of Medicine

St. Louis, MO

Reversing the mislocalization of TorsinA

This study builds on Dr. Hanson’s discovery that localization is a property of TorsinA regulated in the cell and by earlier findings showing that TorsinA is frequently mislocalized. The new study will design a screen to identify new genes that regulate TorsinA activity by controlling where it is located in the cell, looking for new candidates and pathways that may be targets for therapeutic intervention in dystonia.

Christine Klein, MD

University of Luebeck

Germany

Application of next generation sequencing to identify a new dystonia gene

Using the genomes of a family with eight members affected by spasmodic dysphonia, the study seeks to identify a new dystonia gene by applying genome-wide linkage analysis and the latest sequencing techniques to be followed by mutational analysis of the newly identified gene in other dystonia patients. By identifying a novel genetic cause of dystonia, the study may explain many forms of the disease and lead to new therapies.

Antonio Pisani, MD

Fondazione Santa Lucia

Rome, Italy

Evaluating the Role of thalamic activity in the pathogenesis of dystonia

In his previous research into DYT1 dystonia, Dr. Pisani discovered a profound impairment in the synaptic plasticity of the striatum, a brain region involved in motor control. Dr Pisani now seeks to determine whether the aberrant synaptic plasticity of the corticostiatal pathway might lead to an imbalance with the other means of striatal cholinergic transmission, the thalamostriatal pathway. These experiments might have relevant implications for the pathophysiology of dystonia.

A major barrier to the study of dystonia and Parkinson’s in the laboratory has been the inaccessibility of neuronal cells from patients. Now that there is a new technique for creating stem cells, Dr. Taanman will attempts to convert stem cells into neuronal cells affected by rapid-onset dystonia-parkinsonism. This work can open the door to a thorough investigation of the disease mechanism of rapid-onset dystonia-parkinsonism and potentially screen for drugs.

Enrique Torre, PhD

Emory University School of Medicine

Atlanta, GA

The Impact of Mutant TorsinA on the Axon Function

More than 50% of carriers of mutant TorsinA never manifest early onset torsin dystonia (DYT1), but recent imaging studies suggest a deficit in the quality or number of fibers in the axon (the projection of a nerve cell that conducts electrical impulses away from the neuron’s cell body or soma). Dr. Torre will investigate the hypothesis that neurons become vulnerable to stress when expressing a mutated TorsinA, leading to a dysfunctional and/or or dystrophic axon unable to sustain normal synaptic communication or plasticity. These studies will help to understand the role of TorsinA in the normal function of axons and the connections they establish and to design better targeted treatments.

Aziz Ulug, PhD

The Feinstein Institute for Medical Research

Manhasset, NY

Determination of Brain Pathways Involved in Dystonia Using a Mouse Model

Employing a novel experimental approach to validate and expand upon the findings of the human imaging study conducted in DYT1 carriers of dystonia, Dr. Ulug will image DYT1 knockin mice in vitro and ex vitro in order to visualize the white matter pathways that pass through the abnormal brain regions identified in his earlier scans. This study will allow for the direct assessment of the effect of the DYT1 mutation on the structure and function of brain motor pathways.